This cytokine known as IL-15 is a 14-15 KDa glycoprotein, which was simultaneously described by two groups as a T cells-activating growth factor (Grabstein, K. H. et al., Science 1994, 264, 965; Burton, J. D. et al., Proc. Natl. Acad. Sci. USA 1994, 91, 4935). IL-15 mRNA is widely present in cells and tissues, however, it is difficult to find the protein in these cells or in the cells supernatant due to a strong post-transcriptional control of its expression at the translational level and the intracellular traffic (Bamford R N. et al, J. Immunol 1998, 160: 4418-4426), (Kurys G, et al, J Biol Chem 2000, 275: 30653-30659).
The IL-15 biological effects are mediated through its binding to a cell membrane receptor composed of three subunits α, β, and γ. The IL-15Rα is a specific subunit for this cytokine to whom is bound with a very high affinity Kd 10−11, β subunit is shared with IL-2 and γ subunit is a common receptor for several cytokines, IL-2; II-4; IL-7; IL-9; IL-15; IL-21 (Bamford R N., et al, Proc. Natl. Acad. Sci. USA 1994, 91, 4935), (Giri J G., et al, EMBO J. 1995, 14: 3654-3663).
The IL-15 is an immunostimulatory cytokine promoting proliferation and functional activity of T, B and NK cells (Giri, J. G., EMBO J. 1994, 13, 2822-2830), activates neutrophiles and modifies monokine secretion (Girard D., 1996, Blood, 88, 3176; Alleva D. G., 1997, J. Immunol., 159, 2941). This cytokine mediates different effects on several steps of the immune response, induces CD56 NK cells proliferation and acts, together with IL-12, inducing IFNγ and TNFα (Ross M E, 1997, Blood 89, 910-918; Fehniger T A, 1999, Transplant Proc, 31, 1476-1478).
The binding of the ligand to the T cell receptor induces expression of IL-15Rα and expression of several activation antigens such as CD69, CD25 and TNFRII. Also IL-15 is a chemoattractant for human blood T lymphocytes (Wilkinson 1995, J. Exp. Med. 181, 1255-1259). All these data suggest that IL-15 expressed by antigen presenting cells could be important on the early T cell activation at the inflammation site.
II-15 has been detected in the course of several diseases including Crohn's disease (Kirman I., 1996, Am. J. Gastroenterol. 91, 1789), Psoriasis (Rückert R. 2000, 165: 2240-2250), Leukemia (Yamada Y. 1999, Leukemia and Limphoma, 35(1-2): 37-45) and Rheumatoid arthritis (RA), (McInnes I. B. 1998, Immunology Today, 19, 75-79).
Feldmann et al., 1996, Annu Rv Immunol, 14: 397-440) proposed TNFα as the main cytokine in a cytokine cascade that includes IL-1β, IL-6, GM-CSF and several inflammatory cytokines such as Mip 1α, Mip 1β and IL-8, which are closely related to the development and progression of the Rheumatoid arthritis (RA). McInnes et al., found IL-15 expression abnormalities in this disease, high IL-15 concentration in the synovial fluid and its expression in synovial membrane cells. They suggested that IL-15 precedes TNFα in the cytokine cascade, proposing a mechanism dependent on cell contact, where, IL-15 activated T cells induce TNFα synthesis by macrophages. Moreover, it is proposed that IL-15 acts as an important factor on the T cell migration to the synovial fluid (McInnes, 1997, Nat Med, 3: 189-195).
Ziolkowska et al., reported that IL-15 induces IL-17 expression at joints from RA patients, it is already known that this cytokine stimulates release by synoviocytes of several inflammatory mediators such as IL-6, IL-8, GM-CSF, and prostaglandine E2 suggesting an important role for IL-15 in the RA pathogenesis (Ziolkowska y col 2000, J Immunol, 164: 2832-2838).
T cells recruitment and activation may occur as a consequence of IL-15 local synthesis and such non specific activation could bring as a result an endless inflammation. All this suggest that IL-15 inhibition could have a therapeutic potential on the disease treatment.
The use of IL-15 antagonist molecules has been shown to be effective in animal models. Ruchatz et al. generated a soluble fragment from the alpha subunit of the murine receptor (IL-15Rα) and demonstrated that this fragment inhibited collagen-induced arthritis when it was administered to DBA/1 mice (Ruchatz H. 1998, J. Immunol. 160: 5654-5660).
Other IL-15 antagonist molecules have been patented including IL-15 mutated in one or more amino acids residues and monoclonal antibodies capable to bind mature IL-15 and prevent signal transduction through its receptor (U.S. Pat. No. 6,001,973, U.S. Pat. No. 6,177,079, U.S. Pat. No. 6,168,783, and U.S. Pat. No. 6,013,480). Although their use is described in the above mentioned patent files, there are quite a few results published in scientific journals supporting their efficacy. On May 2002, Genmab Company revealed phase I/II clinical studies with an antibody against IL-15 patented by Immunex, which must correspond to previously referred U.S. Pat. No. 6,177,079, but these results have not been published yet.
Other studies have been done with the chimera protein MutIL15-Fc that binds to cells carrying the IL-15 receptor, which leads to a reduced number of activated immune cells below a critical level and induces tolerance, e.g., self-reactive activated T cells with a key role in allograft rejection are responsive to IL-15 and has been demonstrated that they can be inhibited by using MutIL15-Fc protein, which acts as an IL-15 antagonist.
There are a few examples on the vaccine bibliography to generate antibodies against autologous molecules, e.g., a vaccine against EGF for the treatment of EGF dependent tumors (U.S. Pat. No. 5,894,018), its efficacy has been demonstrated in clinical trials by eliciting antibodies that block EGF activity. The generation of neutralizing antibodies against autologous proteins is very complex due to natural mechanisms to tolerate your self